Noninvasive diagnostic imaging of tissues is essential for determining the identification and staging of diseases, and assessing the efficacy of treatment regimens. While most imaging methods provide structural information (CAT, X-Ray, MRI), positron emission tomography permits imaging of regions of specific biochemical activity. Positron emitting radiotracers may be designed to localize in specific tissue types, such as tumors, or they may give a measure of normal metabolic activity. The positron emitting nucleus 18F possesses an ideal half-life (110 minutes) and relatively short positron diffusion distance (1 mm); these features permit relatively high resolution images obtained from [18F]fluorinated radiotracers to be acquired rapidly, with little lingering radioactivity hazard for the patient. Unfortunately, preparation of many desirable [18F]fluoride-labeled radiotracers is stymied by the lack of highly efficient, broadly applicable aromatic radiofluorination methods. The goals of this research project are to develop general methodology to radiofluorinate electron rich aromatic rings with no-carrier-added (n.c.a.) [18F]fluoride and to facilitate general use of this methodology by developing chemistry that interfaces seamlessly with existing commercial automated radiotracer synthesis platforms. This wholly new capability will expand dramatically the types of diseases that can be imaged by PET, and will lead directly to innovative protocols for diagnostic imaging and tissue localization. The proposed research has three specific aims. Specific aim 1 is to develop new, general, highly efficient methodology for single-step iodine-mediated radiofluorination of functionalized, electron-rich aromatic compounds with n.c.a. [18F]fluoride. The proposed work will build on a foundation of mechanistic studies describing the high yield formation of aryl fluorides from the reductive elimination of diaryliodonium fluoride salts. Specific aim 2 is to develop a general synthetic methodology that permits highly functionalized aromatic compounds to be transformed into radiotracer precursors directly. Specific aim 3 is to expand the scope of this synthetic chemistry by providing facile protecting group chemistry that is compatible with late stage radiofluorination of alkaloids.